Cell Culture Media: Balancing Resources with Results

Why does medium matter?

It all starts with media. Without an appropriate growth medium, no biopharmaceutical process would exist. The proper medium allows for cells to grow and generate product. Going beyond the fact that cell culture processes would simply not exist without cell culture media, the medium (and associated feeds for fed-batch processes) represents a large portion of the cost of a biopharmaceutical process. Cell culture media are complex entities that encompass large quantities of raw materials as well as a high level of technical expertise, driving up the cost per litre.

What are the advantages of an optimized medium formulation compared to an off the shelf product? 

Many people will choose to start with standard off the shelf products for their cell culture processes. While there are a wide variety of products available on the market, there are several important reasons to consider using an optimized medium formulation instead. The first is to tailor a medium formulation specifically for your own cell line. Every cell line will respond differently to standard products, and optimizing a medium formulation is the best way to ensure that you use a medium that works best for your application and requirements. Additionally, as you generate different cell lines with varying genetic constructs for new products, your cells may begin to respond differently. Having an optimized medium formulation allows you to adapt to these changes while maintaining growth and productivity. Using a standard product also means you are bound to a single vendor with no access to proprietary formulations. With your own optimized medium, you have full access to the formulation, with the ability to manufacture it with a vendor of your choice.

What factors should I consider when developing an optimized medium?

As discussed previously, optimizing a medium formulation to get you the best growth and productivity is the main driving factor, and allows you to minimize the amount of medium used and therefore your overall COGS. It is important to also consider what the criteria are for your optimized medium. For many industries, having a fully chemically defined, non-animal origin medium is critical. This minimizes lot to lot variability and is highly desirable from a regulatory standpoint. Ease of use is also important to consider. This encompasses storage aspects, such as shelf life, and shipping and handling conditions. Ease of use also involves simplifying the process for the operator. As media and feeds become increasingly complex, how difficult does it become to formulate? Will operators have to perform risky pH adjustments with large volumes of corrosive reagents? Will high temperatures be needed to dissolve certain components, and can these high temperatures be achieved as the industry moves towards more single-use technologies? These and other factors must be considered when developing an optimized medium formulation.

What resources are required to develop an optimized medium?

The actual raw materials that form the bulk of a cell culture medium are generally inexpensive. The resources required for an optimized medium formulation that drive up the ultimate cost per liter are time, personnel, equipment, and expertise. With the increasing use of multivariate approaches (Design of Experiments, Principal Component Analysis), the use of high throughput systems become highly advantageous, reducing personnel requirements. Finally, expertise in media development is something that comes only with years of experience in the industry and cannot be bought with any amount of money.

So how do I develop an optimized medium formulation?

There are several approaches to media optimization. Some methods include titration, reverse engineering of other media, and metabolomics. While some of these methods are effective, when implemented on their own, they are time consuming, labor intensive, and heavily resource-dependent. A modern, DoE based approach to media development for CHO based processes is the CHOptimizer® Media Builder. CHOptimizer® consists of three distinct phases. The package is designed to be integrated into our ambr™15 system for automation and ease of use. In the first phase, four chemically defined, non-animal origin based media are blended in different ratios, according to a mixtures design DoE approach. Subsequent phases incorporate spent media analysis and fractional factorial DoE approaches to develop an optimized medium formulation, feed formulation, and corresponding feeding strategy. CHOptimizer® base media are developed using the expertise of Lonza Biologics, and combines a modern, high throughput approach with traditional ideas to deliver an optimized medium in a short timeline, with field based support. It also offers full access to the formulation for ultimate flexibility in the future.

To learn more about CHO media optimization join Sartorius Stedim Biotech’s workshop, chaired by Dr. Michael Gillmeister, Lonza at the IBC Cell Line Development & Engineering Conference, San Francisco, 13th June at 11.45am.

About the author:

Dr. Michael Gillmeister received his Ph.D. in Chemical and Biomolecular Engineering from the Johns Hopkins University in collaboration with the University of Maryland School of Medicine specializing in glycosylation, transient protein production, and neurobiology. In 2009, Mike joined the Gibco® research and development group and was responsible for next-generation media and sera projects. He then led media and process development projects to modulate product quality and maximize titer for PD-Direct® Custom Media Services using high-throughput and bioreactor technologies. Currently, Mike leads Protein Expression Media R&D and the CHOptimizer™ media optimization service for Lonza Walkersville.

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BioProcess International Conference 2015 - An Overview for Anyone Who Missed It!

by Brandy Sargent

Introduction
While attending this year’s BioProcess International Conference (BPI) in Boston last month, I was excited because it seemed to be a larger turnout then I’d remembered from previous years. BPI recently confirmed that it was in fact the largest attendance in BPI’s twelve-year history. In addition to the larger turnout, the content felt fresher and very relevant to the current challenges and potential solutions facing the industry. BPI provides talks focused on improving the manufacturing process for biopharmaceuticals, enables industry networking opportunities, and the chance to see the latest products and technologies.

Conference Highlights
For me one of the biggest highlights of the conference was the keynote, “Amgen’s Next-Generation Biomanufacturing Facility by Kimball Hall, Vice President Manufacturing, Amgen Singapore Manufacturing Pte. Ltd. In the talk Ms. Hall describes the 200 million dollar next generation manufacturing facility Amgen built in Singapore. The facility was built in less than two years, half the time of a more traditional facility, and is state of the art in terms of innovative technologies. One of the enabling technologies used in the facility is single-use technology. The facility is over 90% single-use, in fact they only need one autoclave. The facility also incorporates continuous processes and relies on the concept of closed system manufacturing.

Ms. Hall describes how they have implemented a closed system approach to allow for a central manufacturing suite where upstream and downstream can be conducted in the same room. They are using smaller, single-use bioreactors coupled with continuous processes in downstream and real time quality analysis to ensure both an efficient process and a closed system. Ms. Hall states that using this manufacturing approach, they have been able to achieve improvements in yield and reduction in cost per gram.

In addition this closed system approach also permits their solution prep area to operate for both media and buffer prep with closed raw material bags, anti-static powder transfer sleeves and connections to 5,000 L single-use mixing vessels ensuring material stays closed within its equipment. To move solutions from the prep room to manufacturing, they have built openings in the walls, which allow solutions to be pumped through this opening into the other room. Material can also be pumped from the central manufacturing suite through an opening in the wall into the final purification room.

Ms. Hall addresses possible environmental impact concerns about the amount of single-use materials by walking through the environmental impact. First, they use less water for heating, cooling and cleaning. The facility overall has a smaller footprint with lower air quality classifications, thus reducing energy consumption and lowering emissions. They have can achieve solid waste reduction due to the smaller reactor size and they are working on recycling the bags and are with a group developing a way to incinerate them for biofuel.

Responding to a question about perceived regulatory risk for this next generation facility, Ms. Hall said that they have met with regulatory bodies along the way, who have been positive but have always said “we’ll have to see on inspection”. They would like it to be licensed as is but have risk mitigation plans in place for how to accommodate any required changes.

One thing that Ms. Hall also makes clear is that the relationships with suppliers have been critical. The suppliers are deeply embedded in this process and she even remarked that there were employees from the supplier companies sitting in her cafeteria during performance lot runs, waiting to help solve any problems that might arise. With the increasing complexity of these technologies, it is key that the relationships with suppliers be strong and that there is trust. Specifications and product details must be shared back and forth so that the best process can be developed and if any problems arise they can be addressed quickly.

As the question and answer session began, one person stood up to ask a question, I’m sorry I didn’t catch her name, but she called the building of this facility “Brave.” Initially it struck me that she used that that term to describe the building of this facility, but upon further reflection I understand why. In building this facility, Amgen has really committed to changing the biomanufacturing paradigm. They have invested incredible amounts of time and resources into a project that has no absolute assurance of regulatory licensing and have shared these details publically as a guide for others. For the industry to evolve it takes a company to embrace new technology and to “go first” to prove that it is feasible and that it can receive approval from the regulatory bodies. The first or firsts must pave the way before others feel comfortable to do it as well. To some in the industry who have been considering this kind of manufacturing platform, but have been waiting to see what will happen, I can see how this move may be considered brave. For a person who has been covering these innovative technologies and was able through Ms. Hall’s talk to see it all put together into one facility, for me it was inspiring.

Another really interesting talk was the keynote on “What is the Future of Continuous Processing – What is the Time Frame for Implementing Fully Continuous Processing in Commercial Production?” by Konstantin Kostantinov, Ph.D., Vice President, Technology Development, Genzyme. Genzyme has long been a proponent and pioneer for continuous processes in biomanufacturing. At the BDP conference earlier this year, there was a wonderful talk given by Dr. Veena Warikoo, Director, Purification Development, Genzyme on their concept of the bioprocessing facility of the future. Please see, “Continuous Bioprocessing – The Biomanufacturing Model of the Future?” for more details.

Other conference highlights this year included:

• Keynote presentations from Merck, Novartis, and the Duke Human Vaccine Institute
• A pre-conference symposium that had an entire track dedicated to Cell Therapy
• Ask the Regulators Open Forum
• Bioprocessing Problem-Solving Moderated Discussions
• Town Hall Forums
• BPI Theater Panel discussions on “Accelerating Biopharmaceutical Development and Manufacturing” and “CMO Panel Discussion on Perspectives and Lessons Learned on Overcoming Challenges with Tech Transfers and Biomanufacturing,”

Different Discussions by Conference Track
There were some overall themes this year that I felt were a continuation of many great discussions that were presented at the BDP Conference earlier this year including continuous processing in both upstream and downstream and implementation of closed systems. This is by no means an exhaustive list, but some highlights of the talks I attended by track include:

Cell Culture

• Perfusion and continuous processes continue to be a hot topic
• Several talks on novel approaches to cell line development including talks on CRISPR/Cas9 technology and how this can be applied to cell line development and production.
• Good discussion surrounding glycolsylation and how to achieve consistentcy. This included discussions around how media is involved in that process and predicting glycosylation profiles using metabolic data.
• Media improvements and using high throughput approaches to process development and media screening.

Recovery and purification

• In downstream, just as in upstream, implementation of continuous processes was a hot topic.
• Several discussions around using new recovery and purification technologies to improve overall efficiency and purification
• Looking at non-chromatographic purification of proteins
• High throughput process development strategies.

Manufacturing strategy

• Facility design incorporating the ballroom suite or central manufacturing suite approach.
• Closed systems as a way to enable more flexible facilities, see “Closed Systems in Biomanufacturing Offer A Variety of Benefits,” for more information.
• Continued process verification (CPV) strategies
• How to utilize facility design, single-use technologies and bioprocess automation in BRIC countries.
• Data collection, data management and bioprocess automation.

Drug Product Manufacturing and Fill-Finish Processing

• Implementing PAT tools and applying QbD
• Streamlining and integrating drug substance and final drug product manufacturing
• New strategies for aseptic filling
• Several talks on particulates and appropriate approaches

Analytical, Formulation and Quality

• Talks on integrating critical quality attribute monitoring and multi-attribute monitoring and control.
• High throughput analytical assays for process development support and quality control
• Many talks on biosimilars and product quality, characterization and comparability.
• Good discussion on supplier relationships and ensuring raw material tracking and control.

I will cover several of these areas in more detail in the coming weeks – stay tuned. In 2016 …

A new BPI West will make its debut March 14-17, 2016 in Oakland, CA and will be the West Coast compliment to BPI in Boston October 4-7, 2016. Register with the code BPIWEST16BL and save $100 off the current rate.


This overview of BPI was contributed by Brandy Sargent, Editor of Cell Culture Dish. View the original post in its entirety here. 

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Bioprocessing Cell Therapy Products Demands Greater Automation

Cell therapy bioprocessing is undergoing significant developments at the moment. Bioprocess engineers that have developed their skills on vaccine or recombinant protein production will recognise the types of challenges experienced by those attempting to manufacture cell therapies, namely, process development, innovation, operations and process transfer, process characterization and the setting of specifications.

Finding solutions to process and technology cell therapy bottlenecks is the topic of a presentation at the Cell Therapy Bioprocessing BPI Boston, Pre-Conference Symposium from invited speaker Nick Timmins. Nick has previously co-authored a review of cell therapy bioprocessing in BioProcess International 12(3) March 2014 entitled ‘Cell Therapy Bioprocessing Technologies and Indicators of Technological Convergence’.

Increased Sensitivity to the Bioprocess Environment

In the review the authors describe how cells in cell therapy bioprocesses are “biologically dynamic” and highly sensitive to the bioprocess environment in which they are produced. This will have a direct impact on a cell therapies critical quality attributes. In contrast, industrial cell lines that are typically used to produce recombinant proteins are more stable during processing and the final protein product are less directly dependent on the culture and processing environment.

Bioprocess automation mitigates risks in patient-specific therapy production

Bioprocessing technologies used for cell therapy manufacture typically require a higher level of automation which allows for a greater level of control of the bioproduction environment which can impact product CQAs, however it also enables operators to run multiple upstream and downstream protocols simultaneously to produce, what could be, patient-specific therapies. The patient-specific nature of some cell therapies adds in an additional layer of complexity to the processing requirements, not typically found in biomanufacturing, driven by the need to prevent the mishandling or cross contamination of patient tissues. Process automation can help mitigate against some of these risks through ensuring the rigorous control and identification of biological materials as they are produced. More manual process interventions increase the opportunities for errors, contaminations and even abuse.  

The BioProcess International Conference and Exposition will be held on October 26-29, 2015 in Boston and the Cell Therapy Pre-Conference Symposium is scheduled to take place on October 26^th.

Dr Nick Hutchinson

Join me at #BPIconf

Contact me at nick.hutchinson@parker.com

Dr Nick Hutchinson has a Masters and Doctorate in Biochemical Engineering from University College London, UK where he focused on laboratory tools for rapid bioprocess development and characterization. He then worked at Lonza Biologics in an R&D function investigating novel methods for large-scale antibody purification before moving to an operational role scaling-up and transferring manufacturing processes between Lonza sites in the UK, Spain and USA. Nick now works in Market Development at Parker domnick hunter where his focus is in bringing Parker's strengths in Motion & Control to Bioprocessing. This will enable customers to improve the quality and deliverability of existing and future biopharmaceuticals.

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BPI 2015 Final program just released!

BPI is engineered to be exactly what YOU need it to be. Formal and informal networking experiences connect you to peers, prospects, and customers. Parallel tracks give you the option to dive deep or take a big picture approach to learn about industry trends, challenges, and benchmark against the latest research developments. Big pharma and large, mid-size and emerging biotechs collaborating with solution providers featuring proven and next generation technologies make BPI a one-of-a-kind meeting place.

Bioprocess International
Conference & Exposition
October 26-29, 2015
Hynes Convention Center
Boston, MA

Download the brochure here: >>> http://bit.ly/1K9ELmX
Use code XB15171BLOG for $100 off the current rate.

The Most Comprehensive Science: Capitalize on the latest data-driven research and moderated discussions to move towards commercialization and streamlined development and production from upstream to drug product/fill-finish. 

The Most Innovative Technologies: Accelerate speed, efficiency and ROI across a global network by evaluating innovative and proven products and services at the industry’s largest exposition.
 

The Right Partners for You: Form collaborations and alliances with innovators, suppliers, academia and associations to reach new heights of clinical and commercial success. 

Gain Access to 6 Conference Tracks with 1 Registration Fee:

• Cell Culture & Upstream Processing;
• Recovery & Purification;
• Manufacturing Strategy;
• Analytical, Formulation and Quality;
• Drug Product Manufacturing & Fill-Finish Processing;
• Early Stage Biologics and Early Stage Companies.   

 Meet the People Behind the Products and Get the Answers You Need!

In the largest exposition hall devoted exclusively to biopharmaceutical manufacturing, attendees will learn about the latest technologies and services developed to overcome challenges and streamline processes. Network and consult with the experts from product and service provider companies.

Download the brochure to learn more: >>> http://bit.ly/1K9ELmX

Register by Friday, June 12 to Receive Up To a $500 Savings
Your Savings Code = XB15171BLOG

Register now to save up to $500 here >>> http://bit.ly/1demU18

Group Rates Available for Companies Registering 4+ Attendees.
Call Millison Thenor directly at 646-895-7423.

*Discount is valid for new registrations only and cannot be combined with any other offer.

Best,
The BPI 2015 Team.
@IBCBioProcess
#BPIconf
www.IBCLifeSciences.com/BPI

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BioProcess International (BPI) 2014 Opens its Doors to More than 1500 Industry Leaders Seeking New Technologies, Partnerships, and Critical insights

Today IBC Life Sciences, is pleased to kick off the 2014 edition of BioProcess International Conference & Exhibition, the world’s largest event dedicated to biological development and manufacturing. Being held at the Hynes Convention Center in Boston from October 20-23, this year’s event will see more than 1500 industry professionals from across the biological development value chain to engage in intensive learning, networking and partnering.

“We are pleased to see that some of the industry’s leading companies have chosen to showcase their new products in the highly anticipated BPI Theater this year. The continued success of the BioProcess International Conference & Exhibition is due to the unwavering commitment of the sponsors, exhibitors, speakers and the attendees who ultimately help to cure disease and improve lives,” said Elizabeth Cutler, Managing Director, IBC Life Sciences.

The event opens with five visionary keynote presentations by John G. Cox, Executive Vice President, Pharmaceutical Operations & Technology, Biogen Idec; Robert Mattaliano, Ph.D., Group Vice President and Head of Biologics, Sanofi-Genzyme R&D Center; and, Geoffrey Ling, M.D., Ph.D., Director, Biological Technologies Office, DARPA.

The four main conference tracks are: cell culture & upstream processing, recovery & purification, manufacturing strategy, formulation & delivery and analytical & quality. These take place on October 21-23.

Plus, IBC will hold pre-conference symposiums on October 20, four bioprocessing professional development training courses on October 20-21 and the new success factors for early stage bilogics and early stage companies session on October 22.

The exhibit hall is open October 21-23 and features 150 exhibitors, the BPI Theater, lounges sponsors by SAFC, Pall Life Sciences and HETIRISK and the emerging marketplace pavilion.
New the year, the BPI Theater located in the exhibit hall (October 22-23) opens with an impressive lineup of new product launches from leading companies including, Meissner Filtration Products, Pall Life Sciences, EMD Millipore, Asahi Kasei Bioprocess, Sartorious Stedim and Purolite.

A high level of productive networking is anticipated by the strong adoption by this year’s attendees of partnering360 event specific networking tool. This new networking tool will make identifying and engaging with best-fit partners at the event easier than ever before.

Plus, the event will be the ideal backdrop to host the BioProcess International 2014 Industry Awards which celebrate and recognize the outstanding people, organizations and technologies that have significantly changed, impacted, and advanced the efficiency of biotherapeutic development and manufacturing process.

We're also onsite covering the event through our social media channels.  Follow #BPIConf on twitter for session updates and visit this blog each morning for a recap of each day's top sessions.

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BioProcess International Conference and Exhibition Starts Next Week!

Next week, over 1,500 bioprocess professionals are gathering in Boston for the industry's #1 bioprocessing event at BioProcess International Conference and Exhibition. Four days of content will will focus on cell culture & upstream processing, recovery & purification, biologics manufacturing strategies, analytical and quality, and formulation and drug delivery. Who else has registered to join us?

Here's some of the companies:

3M Purification, Abbvie. Alexion Pharmaceuticals Inc, Baxter Healthcare Corporation, BD Biosciences, Bio Rad Laboratories, BioProcess Technology Consultants, Bristol Myers Squibb, Chromatan Corporation, Corning Inc, EMD Millipore, Entegris, Eppendorf, Fujifilm Diosynth Biotechnologies, Genentech Incorporated, Hydranautics, Integra Companies Inc, JNC Corporation, Lonza, Merck & Co Inc, Momenta Pharmaceuticals, North Carolina State University, Parker Domnick Hunter, Progentics, Regeneron Pharmaceuticals, SAFC Biosciences, Shire, Takeda Pharmaceutical, United Therapeutics Corporation, VWR International LLC, WuXi AppTec

See a more comprehensive list at the webpage.

Want to join us?  As a reader of this blog, you can still save 20% off standard rates!  Register with priority code BPI14BLOG.  Have any questions?  Email me at jpereira@iirusa.com

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What’s Next in Cell Culture & Upstream Processing?

This fall at BioProcess International, we have a track dedicated to Cell Culture & Upstream Processing.  When you join us to learn about this topic, find out more about proven approaches and technologies to reduce timelines and increase efficiency and productivity.

This October in Boston, we look at

• ● Genomic Tool Implementation
• ● Synthetic Biology Applications
• ● Implementing Continuous Processing for Manufacturing
• ● Commercial Single-Use Applications
• ● Process Intensification
• ● Raw Material Integrity Testing
• ● Media Development and Optimization
• ● Small Scale Models and Tech Transfers

Companies have experienced many recent achievements to improve quality, cost, efficiency and productivity in cell culture, but what impact will the next wave of disruptive technologies and innovations have on biologics production?

Check Out These Key Case Studies & New Data Presentations Featured in these Informative Cell Culture & Upstream Processing Focused Sessions to Find Out: 

• • What's Next In Biologics Production New Data & Case Studies from: SAFC, Amgen and Lily Research Laboratories
• • Improving Product Quality & Control Case Study from: Amgen
• • Innovation at the Interface of Upstream & Downstream Production New Data & Case Studies from: FloDesign Sonic and Bioprocessing Technology Institute
• • Improving Efficiency, Productivity and Timelines in Cell Culture New Data & Case Studies from: Genentech, BioGen Idec and Fujifilm Diosynth Biotechnologies
• • Continuous Processing for Manufacturing (Sponsored by Novasep) New Data & Case Studies from: Sanofi Global Biotherapeutics, Merck & Co, The Pennsylvania State University and BioGen Idec
• • The Next Wave of Single Use Manufacturing: Closed Systems, New Technology and Cost Comparisons (Sponsored by: Life Technologies and Thermo Scientific) New Data & Case Studies from: Biogen Idec and Bayer Healthcare
• • Late Stage Cell Culture New Data & Case Studies from: Alexion Pharmaceuticals, AstraZeneca and Merck Research Labs
• • High-Throughput, QbD and DOE Approaches to Process Development New Data & Case Studies from: Genentech, Biogen Idec and Gallus Biopharmaceuticals

Plus, this Interactive Panel Discussion: How Well do you Know the Raw Materials Used in Your Upstream Manufacturing - Sponsored by BD Bioscience in the Impact of Raw Materials on Product session.

View the Complete Cell Culture Track Agenda

As a reader of this blog, when you register to join us at BioProcess International Conference and Exhibition this October 20-23 in Boston and mention code BPI14BLOG, you can save 20% off the standard rate.  Have any questions or need further information?  Feel free to reach out to Jennifer Pereira.

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Development and Qualification of a Scalable, Disposable Bioreactor for GMP-Compliant Cell Culture

Today, we feature an article from our partners at BioProcessing International Magazine.

Development and Qualification of a Scalable, Disposable Bioreactor for GMP-Compliant Cell Culture

During the past decade, single-use bioreactors have become widely accepted for use in cell culture process development and clinical manufacturing. Their key benefits over stainless steel bioreactors are flexibility, cost, and time savings associated with the reduction of cross contamination risks (1).

Here, we describe our approach to development and qualification of the Biostat STR single-use, stirred-tank bioreactor. Unlike other stirred single-use bioreactors, it offers a similar design to that of well-established, conventional (stainless steel) stirred-tank bioreactors. Disposability of the single-use cultivation chamber gives it robustness, reliability, and reproducibility of biological results together with a supply assurance needed to meet biopharmaceutical industry requirements.

Development of a single-use bioreactor involves different phases of work (Pictured Left). The starting point should be a clear definition of the product’s intended application. Typically, related requirements are captured in a user requirement specification (URS). On the basis of that initial input, the bioreactor design and material selection are then initiated. The proof-of-concept phase establishes component- and product based tests that are predictive of the final application. Mechanical, chemical, and biological tests can be used to verify compliance with the URS during the prototype feasibility phase. Ideally, the production process should be qualified as well: Qualification efforts should cover production equipment, procedures, and parameters. Final product qualification can be based either on qualification of the individual components or the whole final product (or a combination of both) using mechanical and biological tests that emulate a specific intended application. Typically, this evaluation should be performed using bioreactor bags derived from regular manufacturing. All changes brought about (e.g., performance or robustness improvements) should be controlled by a stringent change-control process.

Download the full article here.

Follow the jump for references.

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